Protein folding in the cell

Abstract

In vitro refolding studies are considered as a good model to understand the mechanism by which polypeptide chain acquires unique three dimensional structure in the cell. However, the intracellular environment is highly crowded containing about 300-400 mg/ml of macromolecules. These conditions would promote improper associations among protein molecules leading to aggregation. But protein folds beautifully in the complex cellular environment. This eventually led to the discovery of molecular chaperone that revolutionized the concept of protein folding in the cell. Molecular chaperone is defined as any protein that interacts, stabilizes or helps a non-native protein to acquire the native structure but is not a part of the final structure. Chaperones that participate in protein biogenesis primarily recognize exposed hydrophobic surface of protein and promote their folding through ATP-regulated cycles of binding and release. Failure of the chaperone network to maintain proteostasis, i.e. the conformational integrity of the cellular proteome, may results in the manifestation of pathological states including Parkinson’s  disease,  Huntington’s disease, Alzheimer’s disease  and Amylolateral Sclerosis disease, in which proteins misfold and are deposited as aggregates^[2]. In view of above, in this review, I have discussed current status of protein folding in the cell with special reference to chaperone pathways in de novo folding, chaperones acting downstream of the ribosome, proteostasis network and proteostasis network as drug target.